This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The classical pathological components of Alzheimer's disease (AD), amyloid Beta plaques and neurofibrillary tangles, materialize and persist in the AD brain, invoking chronic inflammatory responses from microglia and astrocytes. These chronic inflammatory responses are widely held to be a primary contributor of insults leading to the damage and death of neurons. Little is known regarding molecular signaling mechanisms leading to the expression of these inflammatory factors. We have completed studies of C/EBP-Beta expression by microglia and C/EBP-epsilon by protoplasmic astrocytes in AD brain tissue. Further, preliminary studies of C/EBP expression in human microglia demonstrate that microglial cells exhibit upregulated expression of C/EBPs in the AD brain and in microglial cultures treated with aggregated A-Beta(1-42) or pro-inflammatory cytokines. In collaboration with Drs. Moeller and Garden at the University of Washington we will continue and extend these studies. Our hypothesis is that CCAAT-Enhancer Binding Protein (C/EBP) family of transcription factors are required for orchestrating glial neuroinflammatory responses in neurodegenerative diseases such as AD. In Specific Aim 1 we will determine whether C/EBPs are upregulated in AD compared to non-demented brain samples (ND-without history or neuropathologic evidence of a neurological disorder). In Specific Aim 2 we will move from postmortem autopsy tissue to glial cell line cultures where specific mechanisms can be tested. Key signaling kinases/proteins critical and intermediate between C/EBP expression/activity and pro- or anti-inflammatory treatments will be determined. The goals of this proposal have both a basic science and translational clinical science emphasis. These emphases are to elucidate at the gene transcriptional level the mechanisms that regulate the expression of inflammatory proteins by glial cells in degenerative diseases. We will examine potential anti-inflammatory drugs which specifically target these processes, thereby dampening neuroinflammation.